Abstract
The repair or misrepair of DNA double-strand breaks (DSBs) largely determines whether a cell will survive radiation insult or die. A new computational model of multicellular, track structure-based and pO2-dependent radiation-induced cell death was developed and used to investigate the contribution to cell killing by the mechanism of DNA free-end misrejoining for low-LET radiation. A simulated tumor of 1224 squamous cells was irradiated with 6 MV x-rays using the Monte Carlo toolkit Geant4 with low-energy Geant4-DNA physics and chemistry modules up to a uniform dose of 1 Gy. DNA damage including DSBs were simulated from ionizations, excitations and hydroxyl radical interactions along track segments through cell nuclei, with a higher cellular pO2 enhancing the conversion of DNA radicals to strand breaks. DNA free-ends produced by complex DSBs (cDSBs) were able to misrejoin and produce exchange-type chromosome aberrations, some of which were asymmetric and lethal. A sensitivity analysis was performed and conditions of full oxia and anoxia were simulated. The linear component of cell killing from misrejoining was consistently small compared to values in the literature for the linear component of cell killing for head and neck squamous cell carcinoma (HNSCC). This indicated that misrejoinings involving DSBs from the same x-ray (including all associated secondary electrons) were rare and that other mechanisms (e.g. unrejoined ends) may be important. Ignoring the contribution by the indirect effect toward DNA damage caused the DSB yield to drop to a third of its original value and the cDSB yield to drop to a tenth of its original value. Track structure-based cell killing was simulated in all 135306 viable cells of a 1 mm3 hypoxic HNSCC tumor for a uniform dose of 1 Gy.
Highlights
One of the tasks of radiobiological modeling is to predict whether a cell that received ionizing radiation will die from the initial radiation-induced DNA damage, broadly consisting of DNA double-strand breaks (DSBs), single-strand breaks, modified bases and modified sugars
This paper presents a new computational model of chromosome aberration (CA) production and cell death from ionizing radiation
The amount of misrejoining and cell killing increased with increasing DSB yield and r0 while the amount of cell killing decreased with increasing Pnlrm, as expected
Summary
One of the tasks of radiobiological modeling is to predict whether a cell that received ionizing radiation will die from the initial radiation-induced DNA damage, broadly consisting of DNA double-strand breaks (DSBs), single-strand breaks, modified bases and modified sugars. Cell death (defined by the loss of replicative potential) after irradiation mainly occurs in the form of mitotic catastrophe, meaning it results from, or follows, aberrant mitosis[1,2,3]. This occurs when a chromosome aberration (CA) is present that is “asymmetric”, preventing a large amount of the genetic material from being replicated. Of the simple exchange-type CAs, dicentrics and rings (centric and acentric) are asymmetric Since they cause a large amount of the genetic material to be lost at the mitosis, they are unstable (lethal).
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